1. Field of the Invention
This invention relates to microscopic-sized starch-based shells (microspheres) and their use in forming microcapsules having utility as delivery systems for drugs, pharmaceuticals, cosmetics and other active agents. These microcapsules (coated droplets) are dispersible in an aqueous carrier and can be used in the preparation of aqueous-based delivery systems of active agents that are lipophilic and water-insoluble in nature. The resultant delivery systems are particularly useful for administration of active agents by injection.
2. Description of the Prior Art
In a three part series of articles discussing the manufacturing techniques for producing microspheres and microcapsules, Arshady [Polymer Eng. & Sci. 29:1746-1758 (1989); and Polymer Eng. & Sci. 30:905-924 (1990)] describes three principal techniques in current practice: (1) suspension cross-linking; (2) coacervation; and (3) solvent evaporation. In suspension cross-linking, a stable droplet suspension of a polymer solution (or melt) is produced in an immiscible liquid, and the droplets are gradually hardened by covalent cross-linking. This process may involve cross-linking of polysaccharides, proteins, or synthetic polymers. Coacervation involves macromolecular aggregation (or phase separation) brought about by partial desolvation of fully solvated macromolecules. Gelatin, gum arabic, and ethylcellulose are commonly used in this process. The solvent extraction/solvent evaporation processes involve droplet formation followed by solvent removal. The extraction or evaporation of the solvent is accompanied by a corresponding decrease in the volume and increase in the viscosity of the individual droplets. Various polysaccharides, polysaccharide derivatives, and synthetic polymers can be used in this technique.
Use of starch as a vehicle for the delivery of drugs and pharmaceuticals is currently limited to only a few specific areas, for example: (1) use of powdered starch (or starch derivatives) in the formulation and pressing of tablets, which are then ingested to deliver their active ingredient; (2) use of capsules that are prepared by molding starch in the presence of plasticizing agents such as water. Capsules are then filled with active ingredient in a separate step. These capsules are thick-walled, have large diameters and also must be ingested to deliver their active ingredient. Neither of these two technologies can be used to deliver drugs or pharmaceuticals by injection.
U.S. Pat. No. 5,676,994, which is incorporated herein by reference, describes compositions prepared by mixing starch, water and a lipophilic component at room temperature and then passing this mixture through an excess steam jet cooker. The resulting jet cooked compositions are stable with respect to separation and coagulation of oil droplets and are comprised of microscopic droplets of oil, about 1-10 microns in diameter, uniformly distributed in the starch-water phase. No emulsifying agents, dispersing agents or surface-active agents are used in the process. The amount of oil in the formulation generally does not exceed 65 parts per 100 parts of starch by weight (about 40% of the total product), and preferred compositions are comprised of about 20-40 parts of oil per 100 parts of starch (17-29%, by weight). The one embodiment that produced a composite containing as much as 90% oil was prepared from a starch-soy protein mixture, rather than pure starch (Example 38 in U.S. Pat. No. 5,676,994). The resulting jet cooked dispersions are useful for a number of end-use applications and are characterized by the following properties: (1) they do not phase separate into their oil and water components on prolonged standing; (2) when cooled, they form soft gels that can be easily converted back to pourable fluids by the application of heat; (3) they may be dried, for example by drum drying, to yield solid compositions that are not oily to the touch; and (4) dried compositions hydrate rapidly and are easily redispersed in water to form smooth, stable, lump-free dispersions that are similar in properties and appearance to aqueous compositions that have never been dried. The electron micrographs in a publication by Eskins et al. (Carbohydrate Polymers, 29: 233-239, 1996) show what appears to be a boundary layer of unknown composition surrounding the lipophilic droplets prepared by the same method as the aforementioned patent. The nature of that boundary layer has not heretofore been characterized.